Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer

Authors: MOON, DAVID - Duke University; HAUCK, J. SPENCER - Duke University; JIANG, XUE - Duke University; QUANG, HOLLY - Baylor College Of Medicine; XU, LINGFAN - Anhui University Of Chinese Medicine; ZHANG, FAN - Duke University; GAO, XIA - Children'S Nutrition Research Center (CNRC); WILD, ROBERT - Dracen Pharmaceuticals, Inc; EVERITT, JEFFREY - Duke University; MACIAS, EVERARDO - Duke University; HE, YIPING - Duke University; HUANG, JIAOTI - Duke University

Submitted to: The Prostate Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2023
Publication Date: 12/12/2023
Citation: Moon, D., Hauck, J., Jiang, X., Quang, H., Xu, L., Zhang, F., Gao, X., Wild, R., Everitt, J.I., Macias, E., He, Y., Huang, J. 2023. Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer. Prostate. 84(4):349–357. https://doi.org/10.1002/pros.24654.
DOI: https://doi.org/10.1002/pros.24654

Interpretive Summary: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. Here we studies the prodrug DRP-104, and we found that DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. We conclude that Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.

Technical Abstract: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCIH660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660. DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.